Trans-dl-1-alkyl-6-alkoxy-1,2,3,4,4a,5,8,8a octa-hydroquinolines

ABSTRACT

A process for preparing 1-alkyl-6-oxodecahydroquinolines in 5 steps--a quaternization, hydrogenation, two organometallic reductions and hydrolysis of the thus formed enol ether--from 6-alkyloxyquinoline and intermediates useful therein.

CROSS-REFERENCE

This application is a division of application Ser. No. 521,863, filedAug. 10, 1983, now U.S. Pat. No. 4,540,787, which was in turn acontinuation-in-part of my copending application Ser. No. 384,817, filedJune 3, 1982, now abandoned.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,198,415 discloses a group ofoctahydropyrazolo[3,4-g]quinolines useful as prolactin inhibitors and inthe treatment of Parkinsonism. The compounds disclosed therein are saidto have D-2 dopamine agonist (dopaminergic) activity, according toTsuruta et al Nature, 292, 463 (1981). One of the more active drugsdisclosed carries an n-propyl group on the quinoline nitrogen.

A key intermediate in the preparation of theseoctahydropyrazolo[3,4-g]quinolines is atrans-dl-1-alkyl-6-oxodecahydroquinoline, one of whose stereoisomers(the 4aα, 8aβ compound) is disclosed in VII of column 5 of U.S. Pat. No.4,198,415. The same intermediate is used to prepare a related group ofcompounds, the 4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinolinesof U.S. Pat. No. 4,235,909, --see compound VII, column 3, lines 50-60(the compound represented by VII is a typographical error since it lacksthe keto group at 6. This error has been noted in the file of U.S. Pat.No. 4,235,909, since it is clear from the context that VII should have aketone group at C-6). The octahydro-2H-pyrrolo[3,4-g]quinolines aresimilar in activity to the octahydro-1H(and2H)-pyrazolo[3,4-g]quinolines in that the compounds are inhibitors ofprolactin secretion and also show activity in experimental models ofParkinson's disease.

U.S. Pat. No. 4,198,415 also discloses the reduction of a mixture ofdouble bond isomers,dl-1-alkyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline anddl-1-alkyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydro quinoline with NaBH₃ CNto yield trans-dl-1-alkyl-6-hydroxydecahydroquinoline.

The hydrogenation of a 6-methoxyquinoline is shown in Honel et al,J.C.S. Perkin I, 1980, 1933. Hydrogenation over platinum in neutral orweakly acidic media results in hydrogenation of the pyridine ring,whereas hydrogenation in acidic (12N HCl or CF₃ COOH) results inhydrogenation of the benzene ring Birch reduction of a6-methoxy-1-benzyl 1,2,3,4-tetrahydroisoquinoline is shown in Okieman etal, J. Roy. Neth. Chem Soc., 99 353 (1980). Reduction of1-methyl-1,2,3,4-tetrahydroquinoline to a mixture of1-methyloctahydroquinolines is shown in Leonard et al, J. Org. Chem. 27,4027 (1962). Lithium and isopropylamine was the reducing agent. In thisinstance, Birch reduction introduced 4 hydrogens into the benzene ring.Birch et al J.C.S., 637 (1971) reduced a series of N,N-dimethylanilineswith Li in liquid ammonia to produce conjugated cyclohexadiene amines.In general, m and p-anisidines (m and p-methoxy dimethyl anilines) gavethe conjugated cyclohexadiene on Birch reduction but the orthoderivative gave the nonconjugated (page 638, formula 3) diene. Reductionof N-(p-methoxyphenyl)morpholine, according to Birch and Dyke, Aust. J.Chem., 31, 1625 (1978) also gave the unconjugated diene on reductionwith Li and liquid NH₃. Both of these reductions involved exocyclicamine functions attached to a benzene ring system containing also ap-methoxy group. Reductions of endocyclic amines, as in an N-alkyl6-methoxytetrahydroquinoline, are not recorded.

Finally Borch et al, J.A.C.S., 93, 2897 (1971) discuss the reduction ofenamines with NaBH₃ CN. No instance of a reduction of an endocyclicdouble bond of an enamine in which the ring contains a second doublebond, has been found.

The method of synthesizing trans-dl-1-alkyl-6-oxodecahydroquinolines, asdisclosed in U.S. Pat. Nos. 4,198,415 and 4,235,909 while operative,involves five steps from a commercially available starting material.Furthermore, yields are not as high as desirable for a commercialprocess.

It is an object of this invention to provide an improved method ofpreparing trans-dl-1-alkyl-6-oxodecahydroquinolines which is easier tocarry out and which gives higher yields than the process previouslyused.

SUMMARY OF THE INVENTION

In fulfillment of the above and other objects, this invention providesan improved method of preparingtrans-dl-1-alkyl-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroquinolines, aracemic mixture. This racemic mixture is comprised of equal amounts oftwo stereoisomers represented by formulas Ia and Ib below. The isomer offormula Ia is named as a1-alkyl-6-oxo-1,2,3,4,4aβ,5,6,7,8,8aα-decahydroquinoline and the isomerof formula Ib is named as atrans-dl-1-alkyl-6-oxo-1,2,3,4,4aα,5,6,7,8,8a8-decahydroquinoline.##STR1##

In the above structures, R is lower alkyl such as methyl, ethyl andn-propyl.

My novel method of preparing this racemate is described, in its broaderaspects, in Flow Chart A which follows: ##STR2## wherein R and R² areseparately C₁₋₃ alkyl, X is a halogen or a pseudohalogen and R¹ is R orallyl.

According to reaction scheme, a 6-alkoxyquinoline such as6-methoxyquinoline (available commercially), is quarternized with analkyl or allyl halide or pseudo halide (R¹ X), preferably an alkyliodide (RI), in an inert solvent such as acetonitrile. The term "pseudohalide" here refers to such nucleophilic (leaving) groups as mesyloxy ortosyloxy which behave chemically in S_(N) 2 reactions like a halidegroup. The quaternization reaction is carried out conveniently at theboiling point of the solvent employed. The quaternary salt (II) is acrystalline material.

In the second step of the synthetic procedure, this salt is hydrogenatedunder pressure using a noble metal catalyst such as platinum (suppliedas PtO₂), palladium, ruthenium or rhodium. This hydrogenation ispreferably carried out in an acidic medium such as glacial acetic acidand at elevated temperatures; i.e., in the range 60°-100° C. Both lowand high pressure reaction conditions are operative; i.e., pressuresvarying from 50-60 psi for low pressure hydrogenation to up to 1000 psifor high pressure hydrogenation are operative. For example, about tenhours are required to reduce one-half mole of II to1-alkyl-6-methoxy-1,2,3,4-tetrahydroquinoline, as the hydrogen iodidesalt (IIIa) at 1000 psi with a PtO₂ catalyst in glacial acetic acid.

The free base (III) is prepared from the salt by treatment of an aqueoussolution of the salt with base followed by extraction of thebase-insoluble tetrahydroquinoline into a water immiscible solvent.

An alternate method of preparing III consists of reduction of6-methoxyquinoline at low pressure over a noble metal catalyst such asPtO₂ in an inert solvent and then alkylating6-methoxy-1,2,3,4-tetrahydroquinoline as with an aldehyde (HCHO, CH₃CHO, C₂ H₅ CHO) under reducing conditions such as low pressurehydrogenation over a noble metal catalyst such as Pd-on-C in an inertsolvent. Useful inert solvents include the lower alkanols, THF, aromatichydrocarbons and the like.

In a second reduction step, the tetrahydroquinoline is reduced underBirch reduction conditions, using an alkali metal, such as sodium orlithium, dissolved in liquid ammonia. The quinoline is customarily addedas a solution in THF to the solution of the alkali metal in liquid NH₃.After the reduction mixture is stirred at liquid ammonia temperaturesfor a suitable period of time, anhydrous ethanol is added until the bluesolution color characteristic of liquid ammonia solution of alkalimetals is discharged. The reaction mixture is then allowed to warm toroom temperature as the NH₃ evaporates. The residual THF solutioncontains a mixture of hexahydroquinolines represented by IVa(1-alkyl-6-alkoxy-1,2,3,4,4aβ,5-hexahydroquinoline), IVb(1-alkyl-6-alkoxy-1,2,3,4,4aα,5-hexahydroquinoline) and IVc(1-alkyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline). This mixture ofhexahydroquinoline isomers is then stereoselectively reduced usingsodium cyanoborohydride or sodium borohydride. A solvent such as THF isemployed in this reduction and a small quantity of glacial acetic acidis also added. The reduction is conveniently carried out at roomtemperature. The borohydride or cyanoborohydride reduction of IVa andIVb to yield an enol ether and the enol ether intermediates producedthereby form a second embodiment of this invention.

The product of the reduction is a racemate, represented by Va and Vbabove Va is named as a1-alkyl-6-alkoxy-1,2,3,4,4aβ,5,8,8aα-octahydroquinoline and Vb is namedas a 1-alkyl-6-alkoxy-1,2,3,4,4aα,5,8,8aβ-octahydroquinoline. Treatmentof this racemate with aqueous acid, preferably HCl, yields a racemicmixture of Ia and Ib, trans-dl -1-alkyl-6-oxodecahydroquinolines.

Preparation of the above compounds is illustrated by the followingspecific Examples.

EXAMPLE 1 Preparation of 1-n-Propyl-6-methoxyquinolinium iodide

Four hundred grams of 6-methoxyquinoline were dissolved in 2.5 l. ofacetonitrile containing 854.4 g. of n-propyl iodide. The resultingsolution was heated to reflux for about 18 hours under a nitrogenblanket. The reaction mixture was cooled and the solvent removed byevaporation in vacuo. The residue was dissolved in acetone and ether wasadded to the point of incipient precipitation. Crystals were produced byscratching. Crystalline 1-n-propyl-6-methoxyquinolinium iodide thusprepared was isolated by filtration; weight=547.2 g.; meltingpoint=111°-115° C. R_(f) (4:1 chloroform:methanol, silica)=0.58. Anadditional 136.2 g. of desired product were obtained from the filtrate.NMR was compatible with the proposed structure.

EXAMPLE 2 Preparation of1-n-Propyl-6-methoxy-1,2,3,4-tetrahydroquinoline

1-n-Propyl-6-methoxyquinolinium iodide was hydrogenated to yield1-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline. In a typical run, 163g. of the quarternary salt were dissolved in 1917 ml. of glacial aceticacid to which were added 20 g. of platinium oxide. Hydrogenation wascarried out at 1000 psi at a temperature of about 100° C. After aboutten hours, the theoretical amount of hydrogen had been absorbed. Thehydrogenation mixture was then filtered to remove the catalyst and thesolvent then removed from the filtrate by evaporation in vacuo. Theresulting residue was dissolved in water and the aqueous solution madebasic by the addition of saturated aqueous sodium bicarbonate. Theaqueous layer was extracted with ether. The ether extracts containing1-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline formed in the abovereaction were washed with water and then dried. The ether was removed byevaporation in vacuo. Ninety-two grams of1-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline were obtained;yield=90.6%.

The above hydrogenation can also be carried at a low pressure such as 60psi. In addition, in place of PtO₂, Pd-on-C can also be used with equalor superior results.

Alternatively, an alkyl halide such as allyl bromide can be used toquaternize the 6-methoxyquinoline since hydrogenation of theN-allyl-6-methoxyquinolinium bromide with a noble metal catalyst such asPtO₂, Pd-on-C, Rb on Al₂ O₃ etc. will ultimately yield the identical1-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline.

EXAMPLE 3 Preparation of1-n-Propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline,1-n-Propyl-6-methoxy-1,2,3,4,4aα,5-hexahydroquinoline and1-n-Propyl-6-methoxy-1,2,3,4,4aβ,5-hexahydroquinoline

Three liters of ammonia were dried over sodium metal for about one hour.800 ml. of ammonia thus dried were then distilled into a 3 l. three-neckflask equipped with gas inlet tube, condenser with drying tube attachedand addition funnel. The ammonia was stirred with a magnetic stirrer. Asolution containing 40 g. of1-n-propyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline in 200 ml. of THF(dry, distilled) were added. Ten g. of lithium metal were cut intochunks of about 1 cc size and these chunks were added in a single batchto the liquid ammonia-tetrahydroquinoline-THF solution. The reactionmixture was stirred for about 20 minutes. Anhydrous ethanol (about 160ml.) was added in dropwise fashion over a 15 minute period. Theresulting mixture was allowed to stir overnight under a nitrogenatmosphere without external cooling. During this time, the ammoniaevaporated. Four-hundred ml. of water were then added. The aqueousmixture was extracted with three 200 ml. portions ofmethylenedichloride. The methylenedichloride layers were combined andthe combined layers washed with 250 ml. of saturated aqueous sodiumchloride. The methylenedichloride layers were then dried and the solventremoved by evaporation in vacuo. The mixture of1-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline,1-n-propyl-6-methoxy-1,2,3,4,4aα,5-hexahydroquinoline and1-n-propyl-6-methoxy-1,2,3,4,4aβ,5-hexahydroquinoline thus produceddistilled in the range 84°-120° C. at a pressure of 0.03 Torr;yield=32.6 g. (80.5%).

EXAMPLE 4 Preparation oftrans-dl-1-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline

A solution was prepared containing 4.4 g. of sodium cyanoborohydride in250 ml. of dried, distilled THF. 14.8 g. of a mixture of1-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline,1-n-propyl-6-methoxy-1,2,3,4,4aα,5-hexahydroquinoline and1-n-propyl-6-methoxy-1,2,3,4,4aβ,5-hexahydroquinoline mixture in 100 ml.of THF were then added, followed by 1.7 ml. of glacial acetic acid. Thereaction mixture was stirred at ambient temperature for about 1.25hours, at which time another 1.7 ml. of glacial acetic acid were added.Stirring was continued for an additional 30 minutes. The entire reactionmixture was then poured into about 300 ml. of water. The aqueous mixturewas extracted three times with 200 ml. of portions ofmethylenedichloride. The organic layers were combined, the combinedlayers were washed once with an equal volume of water and were thendried. The solvent was removed by evaporation in vacuo and the residualyellow viscous oil was distilled.Trans-d1-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline thusprepared distilled in the range 95°-140° C. at 0.2 Torr. or 70°-95° C.at 0.15 Torr. The two distillates were combined, giving a total weightof 10 g. (66% yield). The combined distillates were stored undernitrogen.

Example 5 Alternate preparation oftrans-d1-1-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline

A solution of 10 g. of a mixture of1-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline,1-n-propyl-6-methoxy-1,2,3,4,4aR,5-hexahydroquinoline, and1-n-propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline in 140 ml. ofethanol was prepared. 2.5 ml. of glacial acetic acid were added. Asolution of 1.32 g. of sodium borohydride in ethanol was next addedportionwise to the first solution and the consequent. reaction mixturewas cooled and stirred under nitrogen for about 16 hours.Trans-dl-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline thusprepared was isolated according to the procedure of Example 1;yield=82%.

The above procedure was repeated using 140 ml. of isopropanol in placeof 140 ml. of ethanol, yield=52%; using 140 ml. of methanol, yield=92%;using 40 ml. of ethanol to dissolve the NaBH₄ and 100 ml. of methanol asa solvent, yield=98%.

A run using 10 g. of starting material in 100 ml. of methanol, 1.07 g.of NaBH₄ in 40 ml. of ethanol and 2.8 g. of glacial acetic acid gave a99% yield of the desired 1-n-propyl-6-methoxyoctahydroquinoline.

EXAMPLE 6 Preparation oftrans-dl-1-n-Propyl-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline

A solution was prepared from 3.1 g. oftrans-dl-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline in 25ml. of THF. Four ml. of 10% aqueous sulfuric acid were added. Theresulting two-phase mixture was heated at refluxing temperature forabout 17 hours after which time it was poured into dilute aqueous sodiumhydroxide. The alkaline aqueous mixture was extracted withmethylenedichloride. The methylenedichloride extract was dried and thesolvent removed in vacuo. A residual oil weighing about 2.8 g.comprising trans-dl-1-n-propyl-6-oxodecahydroquinoline distilled in therange 63°-87° C. at 0.1 Torr. TLC indicated that the combined fractionscontained in excess of 90% trans-dl-1-n-propyl-6-oxodecahydroquinoline.

Alternately, 5.0 g. oftrans-dl-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline weredissolved in 50 ml. of THF. Twenty-five ml. of 1N aqueous hydrochloricacid were added and the mixture stirred for one-half hour under anitrogen atmosphere. The reaction mixture was then made basic with 14Naqueous ammonium hydroxide and the alkaline mixture extracted threetimes with methylenedichloride. The organic extracts were combined,dried and the solvent removed in vacuo. 4.8 g. of an orange transparentoil remained as a residue. TLC indicated a single spot at R_(f) =0.67with slight leading and trailing spots as impurities. Distillationyielded trans-dl-1-n-propyl-6-oxodecahydroquinoline boiling at 77°-87°C. at 0.025 Torr. total yield=4.39 g. (94.1%).

EXAMPLE 7

Alternate preparation of1-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline

A solution of 218.5 g. of 6-methoxyquinoline in 1750 ml of methanol washydrogenated at 60 psi over 30 g. of platinum dioxide at 50° overnight.The reaction was filtered and the filtrate concentrated to give an oil.The oil was distilled to give 148.6 g. of6-methoxy-1,2,3,4-tetrahydroquinoline (66% yield) boiling in the range123°-125° C. at 8 Torr.

A solution of 148.6 g. of 6-methoxy-1,2,3,4-tetrahydroquinoline and 58g. of propionaldehyde in 275 ml. of ethanol was hydrogenated at 60 psiover 15 g. of 15% palladium on carbon at room temperature for 2 hoursand then at 50° C. overnight. The catalyst was removed by filtration andthe filtrate concentrated to give a brown oil which was distilled togive 100.5 g. of 6-methoxy-1-n-propyl-1,2,3,4-tetrahydroquinoline (54%yield) as an oil boiling in the range 115°-128° C. at 0.02 Torr.

As previously stated, the products of the synthetic methods of thisinvention, the trans-dl-1-alkyl-6-oxodecahydroquinolines (Ia and Ib),can be reacted with dimethylformamide dimethylacetal to yield atrans-dl-1-alkyl-6-oxo-7-dimethylaminomethylene decahydroquinoline.Reaction of this intermediate with potassium glycinate followed bytreatment with acetic anhydride yields atrans-dl-2-acetyl-5-alkyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.Alkaline hydrolysis of the acetyl derivative yieldstrans-dl-5-alkyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo[3,4-g]quinoline, adopamine agonist useful in treating Parkinsonism or excessive prolactinsecretion (see U.S. Pat. No. 4,235,909). Alternatively, the compoundreacts with hydrazine to yield a tautomeric mixture consisting of transdl-5-alkyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline andthe corresponding 2H compound, useful also as dopamine agonists. (seeU.S. Pat. No. 4,198,415).

I claim:
 1. A compound of the formula ##STR3## wherein R and R² areseparately C₁₋₃ alkyl.
 2. A compound according to claim 1 said compoundbeingtrans-dl-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline.